BLU-451 (EGFR exon 20 insertion inhibitor) ✔️
Blueprint Medicines
Confirmed correct on June 15, 2024 on PubChem.
BLU-451 (formerly LNG-451) is an oral, CNS-penetrant EGFR inhibitor specific for exon 20 insertions. It is being developed by Blueprint Medicines (BPMC 0.00%↑) and is currently in ph1/2 for the treatment of advanced cancers with this mutation (NCT05241873).
Hello darkness my old friend
I feel like my brain’s been so conditioned for the past few months to just take exams that I was worried that I would forget how to get into the Molecular Sherlock flow state. But alas…it is like riding a bicycle.
How I reached my conclusion on this structure is a little bit different than most of posts on here. This is because there was honestly not that much information to draw from. But I made do with the little out there. You can be the judge of whether my thought process makes sense.
Like many of the posts on here, this adventure began with me perusing Espacenent for new solid forms patents. It’s been a while since I’ve done this, so I was sure to find a lot of new stuff. And indeed, I did—including this patent by Blueprint:
A crystalline forms patent with a single structure (Compound 1):
Interesting! First thing’s first: check to see whether this compound has been disclosed yet. I inserted the SMILES formula for this compound 1 into SciFinder, only to find this:
I also checked the SMILES formula in PubChem, which yielded a single result that routed back to the same patent named in the SciFinder result.
So good news for me: it means this compound hasn’t been publicly disclosed yet. Now, I just gotta figure out what compound ID this structure corresponds to. So onto the Blueprint pipeline.
Jigsaw puzzle
From the pipeline, we can see there are 3 named EGFRi candidates: BLU-945, BLU-525, and BLU-451. How do we know which one Compound 1 in the ‘431 patent corresponds to?
First, I did a simple search of each compound. BLU-945 yielded this paper published last year in J. Med. Chem…
…which evidently has a different structure than the ‘431 Compound 1. So this rules BLU-945 out.
So between BLU-525 and BLU-451, which one could the ‘431 Compound 1 correspond to?
Let’s look at the difference between BLU-525 and BLU-451: they say that BLU-451 is specifically designed to be an inhibitor of EGFR with exon 20 insertions.
At this point, I decided to browse the ‘431 patent summary with the hope that it might specify the use. And indeed it does:
So we now know that Compound 1 from the ‘431 crystalline forms patent is intended to target EGFR exon 20 mutant proteins. That rules out BLU-525.
So we’re left with BLU-451. What evidence supports Compound 1 from the ‘431 patent being BLU-451?
Hold on to your hats while I hash this one out.
Hold on to your hats
I mentioned earlier that there’s really not that much biological data to draw from for this Compound 1. The most that’s disclosed in the patents are cell based IC50 data, which is honestly not super helpful.
In the ‘431 patent, I went to the ISR at the end with the hope of finding connected patents which would have biological data. But all I found was this:
At first, I was surprised that there were no related Blueprint patents. As you can see, I highlighted the ones by Lengo Therapeutics, because I later found out that Blueprint acquired Lengo back in December 2021:
So from the SEC 10K, I now knew that BLU-415 = LNG-451. Knowing this, I returned to the ISR at the end of the ‘431 patent and looked into the Lengo patent WO2022094354 first because the ISR cited a specific example (example 27).
BUT when I went to example 27, I found a DIFFERENT compound than the Compound 1 described in ‘431:
Completely different structure. So I scoured through the rest of the example compounds to make sure that I wasn’t missing anything. Lo and behold, it turns out example 37 = Compound 1 from ‘431.
So that goes to show you that these patent search committees get things wrong too. Kind of annoying, actually.
From the ‘431 patent we also know that Compound 1 is designed to be CNS-penetrant:
This detail is important because we know that BLU-451 is designed to be CNS-penetrant:
So to summarize, at this point we know the following:
BLU-451 = LNG-451
Example 37 in the Lengo ‘354 patent = Compound 1 in the Blueprint ‘431 crystalline forms patent
Compound 1 in the ‘431 patent = designed to be brain-penetrant
Compound 1 in the ‘431 patent is an inhibitor specific for EGFR exon 20 insertion. BLU-451 is an inhibitor specific for EGFR exon 20 insertion.
The last piece that we’re missing is the connection between the biological data and the chemical structure. As I said, the corroborating biological data in the patents is almost non-existent for this compound, so bear with me here.
Blueprint has presented on BLU-451 in several posters (obviously without disclosing structure). One poster in particular that I found interesting was presented at AACR in 2022:
The only biological data we have in the patents is cell culture-based IC50 values. While this poster does not explicitly list IC50 values, it provides a bar graph for IC50 values across several cell lines:
We also have IC50 values for Compound 1 (aka, example 37) in the Lengo ‘354 patent:
If we compare the cell lines between the AACR 2022 poster and the ‘354 patent, we see similarities:
So, this tells us:
NPH line in the ‘354 patent = NPH line in the AACR 2022 poster.
D770 line in the ‘354 patent could be either the SVD or SVD-Ph line in the AACR 2022 poster.
Since we have actual numerical values of Compound 1 (example 37) in these cell lines in the ‘354 patent, we can see how they stack up to the plotted bar values in the AACR 2022 poster using a plot digitizer.
And while it does not come to the exact same value, one can appreciate the similarities:
Admittedly it is a bit off. But again, to summarize:
BLU-451 = LNG-451
Example 37 in the Lengo ‘354 patent = Compound 1 in the Blueprint ‘431 crystalline forms patent
Compound 1 in the ‘431 patent = designed to be brain-penetrant
Compound 1 in the ‘431 patent is an inhibitor specific for EGFR exon 20 insertion. BLU-451 is an inhibitor specific for EGFR exon 20 insertion.
Similar IC50 values +/- 10 nM in the same cell lines.
So all this taken together, I am fairly comfortable in calling Compound 1 (example 37) = BLU-451.
And there you have it. Thanks again for all your patience. It’s good to be back! On to the next. 👉😎👉
Have a compound that you want me look into? Suggest a compound here.